cGAS-STING and autophagy: crosstalk, molecular mechanisms, and targeted therapy.

Abstract

The cytosolic DNA-sensing cGAS-STING pathway and autophagy represent two evolutionarily conserved systems critical for innate immunity and cellular homeostasis. The cGAS-STING pathway detects mislocalized DNA, triggering inflammation via interferon and cytokine production. Conversely, autophagy maintains equilibrium by degrading damaged organelles and pathogens. Crucially, these systems engage in reciprocal regulation: autophagy constrains cGAS-STING hyperactivity through lysosomal degradation of immunostimulatory DNA and STING itself, while cGAS-STING signaling induces autophagy via TBK1-mediated phosphorylation of autophagy adaptors to mitigate self-damage. Dysregulation of this interplay drives pathology. For instance, defective autophagy in systemic lupus erythematosus permits mitochondrial DNA accumulation and cGAS-driven interferonopathy, whereas persistent STING activation in cancers suppresses autophagic tumor surveillance. This review aims to dissect the molecular mechanisms underpinning their crosstalk, delineate its disruption in autoimmune, neurodegenerative, and oncological diseases, and critically evaluate emerging therapies designed to pharmacologically rebalance this axis. These include combining cGAS-STING inhibitors with autophagy enhancers to suppress inflammation in interferonopathies, and pairing STING agonists with autophagy inducers to potentiate antitumor immunity.By synthesizing preclinical and clinical advances, we establish a framework for developing context-specific therapeutics that exploit the cGAS-STING-autophagy circuit-translating mechanistic insights into precision treatments for immune dysregulation disorders.